1  488 153 ASSESSING DIAGNOSTIC VALUE OF MICRORNAS FROM PERIPHERAL BLOOD MONONUCLEAR CELLS AND EXTRACELLULAR VESICLES IN MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME. MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A DEBILITATING MULTISYSTEMIC DISEASE OF UNKNOWN ETIOLOGY, AFFECTING THOUSANDS OF INDIVIDUALS WORLDWIDE. ITS DIAGNOSIS STILL RELIES ON RULING OUT MEDICAL PROBLEMS LEADING TO UNEXPLAINED FATIGUE DUE TO A COMPLETE LACK OF DISEASE-SPECIFIC BIOMARKERS. OUR GROUP AND OTHERS HAVE EXPLORED THE POTENTIAL VALUE OF MICRORNA PROFILES (MIRNOMES) AS DIAGNOSTIC TOOLS FOR THIS DISEASE. HOWEVER, HETEROGENEITY OF PARTICIPANTS, LOW NUMBERS, THE VARIETY OF SAMPLES ASSAYED, AND OTHER PRE-ANALYTICAL VARIABLES, HAVE HAMPERED THE IDENTIFICATION OF DISEASE-ASSOCIATED MIRNOMES. IN THIS STUDY, OUR TEAM HAS EVALUATED, FOR THE FIRST TIME, ME/CFS MIRNOMES IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) AND EXTRACELLULAR VESICLES (EVS) FROM SEVERELY ILL PATIENTS RECRUITED AT THE MONOGRAPHIC UK ME BIOBANK TO ASSESS, USING STANDARD OPERATING PROCEDURES (SOPS), BLOOD FRACTIONS WITH OPTIMAL DIAGNOSTIC POWER FOR A RAPID TRANSLATION OF A MIR-BASED DIAGNOSTIC METHOD INTO THE CLINIC. OUR RESULTS SHOW THAT ROUTINE CREATINE KINASE (CK) BLOOD VALUES, PLASMA EVS PHYSICAL CHARACTERISTICS (INCLUDING COUNTS, SIZE AND ZETA-POTENTIAL), AND A LIMITED NUMBER OF DIFFERENTIALLY EXPRESSED PBMC AND EV MIRNAS APPEAR SIGNIFICANTLY ASSOCIATED WITH SEVERE ME/CFS (P < 0.05). GENE ENRICHMENT ANALYSIS POINTS TO EPIGENETIC AND NEUROIMMUNE DYSREGULATED PATHWAYS, IN AGREEMENT WITH PREVIOUS REPORTS. POPULATION VALIDATION BY A COST-EFFECTIVE APPROACH LIMITED TO THESE FEW POTENTIALLY DISCRIMINATING VARIABLES IS GRANTED.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
2 3496  53 IDENTIFICATION OF MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME-ASSOCIATED DNA METHYLATION PATTERNS. BACKGROUND: MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A COMPLEX CONDITION INVOLVING MULTIPLE ORGAN SYSTEMS AND CHARACTERIZED BY PERSISTENT/RELAPSING DEBILITATING FATIGUE, IMMUNE DYSFUNCTION, NEUROLOGICAL PROBLEMS, AND OTHER SYMPTOMS NOT CURABLE FOR AT LEAST 6 MONTHS. DISRUPTION OF DNA METHYLATION PATTERNS HAS BEEN TIED TO VARIOUS IMMUNE AND NEUROLOGICAL DISEASES; HOWEVER, ITS STATUS IN ME/CFS REMAINS UNCERTAIN. OUR STUDY AIMED AT IDENTIFYING CHANGES IN THE DNA METHYLATION PATTERNS THAT ASSOCIATE WITH ME/CFS. METHODS: WE EXTRACTED GENOMIC DNA FROM PERIPHERAL BLOOD MONONUCLEAR CELLS FROM 13 ME/CFS STUDY SUBJECTS AND 12 HEALTHY CONTROLS AND MEASURED GLOBAL DNA METHYLATION BY ELISA-LIKE METHOD AND SITE-SPECIFIC METHYLATION STATUS USING ILLUMINA METHYLATIONEPIC MICROARRAYS. PYROSEQUENCING VALIDATION INCLUDED 33 ME/CFS CASES AND 31 CONTROLS FROM TWO GEOGRAPHICALLY DISTANT COHORTS. RESULTS: GLOBAL DNA METHYLATION LEVELS OF ME/CFS CASES WERE SIMILAR TO THOSE OF CONTROLS. HOWEVER, MICROARRAY-BASED APPROACH ALLOWED DETECTION OF 17,296 DIFFERENTIALLY METHYLATED CPG SITES IN 6,368 GENES ACROSS REGULATORY ELEMENTS AND WITHIN CODING REGIONS OF GENES. ANALYSIS OF DNA METHYLATION IN PROMOTER REGIONS REVEALED 307 DIFFERENTIALLY METHYLATED PROMOTERS. INGENUITY PATHWAY ANALYSIS INDICATED THAT GENES ASSOCIATED WITH DIFFERENTIALLY METHYLATED PROMOTERS PARTICIPATED IN AT LEAST 15 DIFFERENT PATHWAYS MOSTLY RELATED TO CELL SIGNALING WITH A STRONG IMMUNE COMPONENT. CONCLUSIONS: THIS IS THE FIRST STUDY THAT HAS EXPLORED GENOME-WIDE EPIGENETIC CHANGES ASSOCIATED WITH ME/CFS USING THE ADVANCED ILLUMINA METHYLATIONEPIC MICROARRAYS COVERING ABOUT 850,000 CPG SITES IN TWO GEOGRAPHICALLY DISTANT COHORTS OF ME/CFS CASES AND MATCHED CONTROLS. OUR RESULTS ARE ALIGNED WITH PREVIOUS STUDIES THAT INDICATE A DYSREGULATION OF THE IMMUNE SYSTEM IN ME/CFS. THEY ALSO SUGGEST A POTENTIAL ROLE OF EPIGENETIC DE-REGULATION IN THE PATHOBIOLOGY OF ME/CFS. WE PROPOSE SCREENING OF LARGER COHORTS OF ME/CFS CASES TO DETERMINE THE EXTERNAL VALIDITY OF THESE EPIGENETIC CHANGES IN ORDER TO IMPLEMENT THEM AS POSSIBLE DIAGNOSTIC MARKERS IN CLINICAL SETTING.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
3 1519  34 DNA METHYLATION AT ATP11A CG11702988 IS A BIOMARKER OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS: A LONGITUDINAL STUDY. CYSTIC FIBROSIS (CF) IS A CHRONIC GENETIC DISEASE THAT MAINLY AFFECTS THE RESPIRATORY AND GASTROINTESTINAL SYSTEMS. NO CURATIVE TREATMENTS ARE AVAILABLE, BUT THE FOLLOW-UP IN SPECIALIZED CENTERS HAS GREATLY IMPROVED THE PATIENT LIFE EXPECTANCY. ROBUST BIOMARKERS ARE REQUIRED TO MONITOR THE DISEASE, GUIDE TREATMENTS, STRATIFY PATIENTS, AND PROVIDE OUTCOME MEASURES IN CLINICAL TRIALS. IN THE PRESENT STUDY, WE OUTLINE A STRATEGY TO SELECT PUTATIVE DNA METHYLATION BIOMARKERS OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS PATIENTS. IN THE DISCOVERY STEP, WE SELECTED SEVEN POTENTIAL BIOMARKERS USING A GENOME-WIDE DNA METHYLATION DATASET THAT WE GENERATED IN NASAL EPITHELIAL SAMPLES FROM THE METHYLCF COHORT. IN THE REPLICATION STEP, WE ASSESSED THE SAME BIOMARKERS USING SPUTUM CELL SAMPLES FROM THE METHYLBIOMARK COHORT. OF INTEREST, DNA METHYLATION AT THE CG11702988 SITE (ATP11A GENE) POSITIVELY CORRELATED WITH LUNG FUNCTION AND BMI, AND NEGATIVELY CORRELATED WITH LUNG DISEASE SEVERITY, P. AERUGINOSA CHRONIC INFECTION, AND THE NUMBER OF EXACERBATIONS. THESE RESULTS WERE REPLICATED IN PROSPECTIVE SPUTUM SAMPLES COLLECTED AT FOUR TIME POINTS WITHIN AN 18-MONTH PERIOD AND LONGITUDINALLY. TO CONCLUDE, (I) WE IDENTIFIED A DNA METHYLATION BIOMARKER THAT CORRELATES WITH CF SEVERITY, (II) WE PROVIDED A METHOD TO EASILY ASSESS THIS BIOMARKER, AND (III) WE CARRIED OUT THE FIRST LONGITUDINAL ANALYSIS OF DNA METHYLATION IN CF PATIENTS. THIS NEW EPIGENETIC BIOMARKER COULD BE USED TO STRATIFY CF PATIENTS IN CLINICAL TRIALS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
4 3041  33 GENOME-EPIGENOME INTERACTIONS ASSOCIATED WITH MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME. MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A COMPLEX DISEASE OF UNKNOWN ETIOLOGY. MULTIPLE STUDIES POINT TO DISRUPTIONS IN IMMUNE FUNCTIONING IN ME/CFS PATIENTS AS WELL AS SPECIFIC GENETIC POLYMORPHISMS AND ALTERATIONS OF THE DNA METHYLOME IN LYMPHOCYTES. HOWEVER, POTENTIAL INTERACTIONS BETWEEN DNA METHYLATION AND GENETIC BACKGROUND IN RELATION TO ME/CFS HAVE NOT BEEN EXAMINED. IN THIS STUDY WE EXPLORED THIS ASSOCIATION BY CHARACTERIZING THE EPIGENETIC (~480 THOUSAND CPG LOCI) AND GENETIC (~4.3 MILLION SNPS) VARIATION BETWEEN COHORTS OF ME/CFS PATIENTS AND HEALTHY CONTROLS. WE FOUND SIGNIFICANT ASSOCIATIONS OF DNA METHYLATION STATES IN T-LYMPHOCYTES AT SEVERAL CPG LOCI AND REGIONS WITH ME/CFS PHENOTYPE. THESE METHYLATION ANOMALIES ARE IN CLOSE PROXIMITY TO GENES INVOLVED WITH IMMUNE FUNCTION AND CELLULAR METABOLISM. FINALLY, WE FOUND SIGNIFICANT CORRELATIONS OF GENOTYPES WITH METHYLATION MODIFICATIONS ASSOCIATED WITH ME/CFS. THE FINDINGS FROM THIS STUDY HIGHLIGHT THE ROLE OF EPIGENETIC AND GENETIC INTERACTIONS IN COMPLEX DISEASES, AND SUGGEST SEVERAL GENETIC AND EPIGENETIC ELEMENTS POTENTIALLY INVOLVED IN THE MECHANISMS OF DISEASE IN ME/CFS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
5 1699  30 DYNAMIC EPIGENETIC CHANGES DURING A RELAPSE AND RECOVERY CYCLE IN MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME. MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A COMPLEX DISEASE WITH VARIABLE SEVERITY. PATIENTS EXPERIENCE FREQUENT RELAPSES WHERE SYMPTOMS INCREASE IN SEVERITY, LEAVING THEM WITH A MARKED REDUCTION IN QUALITY OF LIFE. PREVIOUS WORK HAS INVESTIGATED MOLECULAR DIFFERENCES BETWEEN ME/CFS PATIENTS AND HEALTHY CONTROLS, BUT NOT THE DYNAMIC CHANGES SPECIFIC TO EACH INDIVIDUAL PATIENT. WE APPLIED PRECISION MEDICINE HERE TO MAP GENOMIC CHANGES IN TWO SELECTED ME/CFS PATIENTS THROUGH A PERIOD THAT CONTAINED A RELAPSE RECOVERY CYCLE. DNA WAS ISOLATED FROM TWO PATIENTS AND A HEALTHY AGE/GENDER MATCHED CONTROL AT REGULAR INTERVALS AND CAPTURED THE PATIENT RELAPSE IN EACH CASE. REDUCED REPRESENTATION DNA METHYLATION SEQUENCING PROFILES WERE OBTAINED SPANNING THE RELAPSE RECOVERY CYCLE. BOTH PATIENTS SHOWED A SIGNIFICANTLY LARGER METHYLOME VARIABILITY (10-20-FOLD) THROUGH THE PERIOD OF SAMPLING COMPARED WITH THE CONTROL. DURING THE RELAPSE, CHANGES IN THE METHYLOME PROFILES OF THE TWO PATIENTS WERE DETECTED IN REGULATORY-ACTIVE REGIONS OF THE GENOME THAT WERE ASSOCIATED, RESPECTIVELY, WITH 157 AND 127 DOWNSTREAM GENES, INDICATING DISTURBED METABOLIC, IMMUNE AND INFLAMMATORY FUNCTIONS. SEVERE HEALTH RELAPSES IN THE ME/CFS PATIENTS RESULTED IN FUNCTIONALLY IMPORTANT CHANGES IN THEIR DNA METHYLOMES THAT, WHILE DIFFERING BETWEEN THE TWO PATIENTS, LED TO VERY SIMILAR COMPROMISED PHYSIOLOGY. DNA METHYLATION AS A SIGNATURE OF DISEASE VARIABILITY IN ONGOING ME/CFS MAY HAVE PRACTICAL APPLICATIONS FOR STRATEGIES TO DECREASE RELAPSE FREQUENCY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
6 2207  49 EPIGENETIC MODIFICATIONS AND GLUCOCORTICOID SENSITIVITY IN MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS). BACKGROUND: MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A DEBILITATING IDIOPATHIC DISEASE CHARACTERIZED BY UNEXPLAINED FATIGUE THAT FAILS TO RESOLVE WITH SUFFICIENT REST. DIAGNOSIS IS BASED ON A LIST OF SYMPTOMS AND EXCLUSION OF OTHER FATIGUE-RELATED HEALTH CONDITIONS. DESPITE A HETEROGENEOUS PATIENT POPULATION, IMMUNE AND HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS FUNCTION DIFFERENCES, SUCH AS ENHANCED NEGATIVE FEEDBACK TO GLUCOCORTICOIDS, ARE RECURRING FINDINGS IN ME/CFS STUDIES. EPIGENETIC MODIFICATIONS, SUCH AS CPG METHYLATION, ARE KNOWN TO REGULATE LONG-TERM PHENOTYPIC DIFFERENCES AND PREVIOUS WORK BY OUR GROUP FOUND DNA METHYLOME DIFFERENCES IN ME/CFS, HOWEVER THE RELATIONSHIP BETWEEN DNA METHYLOME MODIFICATIONS, CLINICAL AND FUNCTIONAL CHARACTERISTICS ASSOCIATED WITH ME/CFS HAS NOT BEEN EXAMINED. METHODS: WE EXAMINED THE DNA METHYLOME IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) OF A LARGER COHORT OF FEMALE ME/CFS PATIENTS USING THE ILLUMINA HUMANMETHYLATION450 BEADCHIP ARRAY. IN PARALLEL TO THE DNA METHYLOME ANALYSIS, WE INVESTIGATED IN VITRO GLUCOCORTICOID SENSITIVITY DIFFERENCES BY STIMULATING PBMCS WITH PHYTOHAEMAGGLUTININ AND SUPPRESSED GROWTH WITH DEXAMETHASONE. WE EXPLORED DNA METHYLATION DIFFERENCES USING BISULFITE PYROSEQUENCING AND STATISTICAL PERMUTATION. LINEAR REGRESSION WAS IMPLEMENTED TO DISCOVER EPIGENOMIC REGIONS ASSOCIATED WITH SELF-REPORTED QUALITY OF LIFE AND NETWORK ANALYSIS OF GENE ONTOLOGY TERMS TO BIOLOGICALLY CONTEXTUALIZE RESULTS. RESULTS: WE DETECTED 12,608 DIFFERENTIALLY METHYLATED SITES BETWEEN ME/CFS PATIENTS AND HEALTHY CONTROLS PREDOMINANTLY LOCALIZED TO CELLULAR METABOLISM GENES, SOME OF WHICH WERE ALSO RELATED TO SELF-REPORTED QUALITY OF LIFE HEALTH SCORES. AMONG ME/CFS PATIENTS, GLUCOCORTICOID SENSITIVITY WAS ASSOCIATED WITH DIFFERENTIAL METHYLATION AT 13 LOCI. CONCLUSIONS: OUR RESULTS INDICATE DNA METHYLATION MODIFICATIONS IN CELLULAR METABOLISM IN ME/CFS DESPITE A HETEROGENEOUS PATIENT POPULATION, IMPLICATING THESE PROCESSES IN IMMUNE AND HPA AXIS DYSFUNCTION IN ME/CFS. MODIFICATIONS TO EPIGENETIC LOCI ASSOCIATED WITH DIFFERENCES IN GLUCOCORTICOID SENSITIVITY MAY BE IMPORTANT AS BIOMARKERS FOR FUTURE CLINICAL TESTING. OVERALL, THESE FINDINGS ALIGN WITH RECENT ME/CFS WORK THAT POINT TOWARDS IMPAIRMENT IN CELLULAR ENERGY PRODUCTION IN THIS PATIENT POPULATION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
7 2050  34 EPIGENETIC COMPONENTS OF MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME UNCOVER POTENTIAL TRANSPOSABLE ELEMENT ACTIVATION. PURPOSE: STUDIES TO DETERMINE EPIGENETIC CHANGES ASSOCIATED WITH MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) REMAIN SCARCE; HOWEVER, CURRENT EVIDENCE CLEARLY SHOWS THAT METHYLATION PATTERNS OF GENOMIC DNA AND NONCODING RNA PROFILES OF IMMUNE CELLS DIFFER BETWEEN PATIENTS AND HEALTHY SUBJECTS, SUGGESTING AN ACTIVE ROLE OF THESE EPIGENETIC MECHANISMS IN THE DISEASE. THE PRESENT STUDY COMPARES AND CONTRASTS THE AVAILABLE ME/CFS EPIGENETIC DATA IN AN EFFORT TO EVIDENCE OVERLAPPING PATHWAYS CAPABLE OF EXPLAINING AT LEAST SOME OF THE DYSFUNCTIONAL IMMUNE PARAMETERS LINKED TO THIS DISEASE. METHODS: A SYSTEMATIC SEARCH OF THE LITERATURE EVALUATING THE ME/CFS EPIGENOME LANDSCAPE WAS PERFORMED FOLLOWING THE PREFERRED REPORTING ITEMS FOR SYSTEMATIC REVIEWS AND META-ANALYSES CRITERIA. DIFFERENTIAL DNA METHYLATION AND NONCODING RNA DIFFERENTIAL EXPRESSION PATTERNS ASSOCIATED WITH ME/CFS WERE USED TO SCREEN FOR THE PRESENCE OF TRANSPOSABLE ELEMENTS USING THE DFAM BROWSER, A SEARCH PROGRAM NURTURED WITH THE REPBASE REPETITIVE SEQUENCE DATABASE AND THE REPEATMASKER ANNOTATION TOOL. FINDINGS: UNEXPECTEDLY, PARTICULAR ASSOCIATIONS OF TRANSPOSABLE ELEMENTS AND ME/CFS EPIGENETIC HALLMARKS WERE UNCOVERED. A MODEL FOR THE DISEASE EMERGED INVOLVING TRANSCRIPTIONAL INDUCTION OF ENDOGENOUS DORMANT TRANSPOSONS AND STRUCTURED CELLULAR RNA INTERACTIONS, TRIGGERING THE ACTIVATION OF THE INNATE IMMUNE SYSTEM WITHOUT A CONCOMITANT ACTIVE INFECTION. IMPLICATIONS: REPETITIVE SEQUENCE FILTERS (IE, REPEATMASKER) SHOULD BE AVOIDED WHEN ANALYZING TRANSCRIPTOMIC DATA TO ASSESS THE POTENTIAL PARTICIPATION OF REPETITIVE SEQUENCES ("JUNK REPETITIVE DNA"), REPRESENTING >45% OF THE HUMAN GENOME, IN THE ONSET AND EVOLUTION OF ME/CFS. IN ADDITION, TRANSPOSABLE ELEMENT SCREENINGS AIMED AT DESIGNING COST-EFFECTIVE, FOCUSED EMPIRICAL ASSAYS THAT CAN CONFIRM OR DISPROVE THE SUSPECTED INVOLVEMENT OF TRANSPOSON TRANSCRIPTIONAL ACTIVATION IN THIS DISEASE, FOLLOWING THE PILOT STRATEGY PRESENTED HERE, WILL REQUIRE DATABASES GATHERING LARGE ME/CFS EPIGENETIC DATASETS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
8 1601  33 DNA METHYLATION SIGNATURES OF FUNCTIONAL SOMATIC SYNDROMES: SYSTEMATIC REVIEW. OBJECTIVE: FUNCTIONAL SOMATIC SYNDROMES (FSS) ARE HIGHLY PREVALENT ACROSS ALL LEVELS OF HEALTHCARE. THE FACT THAT THEY ARE CHARACTERISED BY MEDICALLY UNEXPLAINED SYMPTOMS, SUCH AS FATIGUE AND PAIN, RAISES THE IMPORTANT QUESTION OF THEIR UNDERLYING PATHOPHYSIOLOGY. PSYCHOSOCIAL STRESS REPRESENTS A SIGNIFICANT FACTOR IN THE DEVELOPMENT OF FSS AND CAN INDUCE LONG-TERM MODIFICATIONS AT THE EPIGENETIC LEVEL. THE AIM OF THIS REVIEW WAS TO SYSTEMATICALLY REVIEW, FOR THE FIRST TIME, WHETHER INDIVIDUALS WITH FSS ARE CHARACTERISED BY SPECIFIC ALTERATIONS IN DNA METHYLATION. METHODS: MEDLINE AND PSYCINFO WERE SEARCHED FROM THE FIRST AVAILABLE DATE UNTIL SEPTEMBER 2022. THE INCLUSION CRITERIA WERE: 1) ADULTS FULFILLING RESEARCH DIAGNOSTIC CRITERIA FOR CHRONIC FATIGUE SYNDROME, FIBROMYALGIA SYNDROME, AND/OR IRRITABLE BOWEL SYNDROME, 2) HEALTHY CONTROL GROUP, AND 3) CANDIDATE-GENE OR GENOME-WIDE STUDY OF DNA METHYLATION. RESULTS: SIXTEEN STUDIES (N = 957) WERE INCLUDED. IN CANDIDATE-GENE STUDIES, SPECIFIC SITES WITHIN NR3C1 WERE IDENTIFIED, WHICH WERE HYPOMETHYLATED IN INDIVIDUALS WITH CHRONIC FATIGUE SYNDROME COMPARED TO HEALTHY CONTROLS. IN GENOME-WIDE STUDIES IN CHRONIC FATIGUE SYNDROME, A HYPOMETHYLATED SITE LOCATED TO LY86 AND HYPERMETHYLATED SITES WITHIN HLA-DQB1 WERE FOUND. IN GENOME-WIDE STUDIES IN FIBROMYALGIA SYNDROME, DIFFERENTIAL METHYLATION IN SITES RELATED TO HDAC4 , TMEM44 , KCNQ1 , SLC17A9 , PRKG1 , ALPK3 , TFAP2A , AND LY6G5C WAS FOUND. CONCLUSIONS: INDIVIDUALS WITH CHRONIC FATIGUE SYNDROME AND FIBROMYALGIA SYNDROME APPEAR TO BE CHARACTERISED BY ALTERED DNA METHYLATION OF GENES REGULATING CELLULAR SIGNALLING AND IMMUNE FUNCTIONING. IN CHRONIC FATIGUE SYNDROME, THERE IS PRELIMINARY EVIDENCE FOR THESE TO BE IMPLICATED IN KEY PATHOPHYSIOLOGICAL ALTERATIONS, SUCH AS HYPOCORTISOLISM AND LOW-GRADE INFLAMMATION, AND TO CONTRIBUTE TO THE DEBILITATING SYMPTOMS THESE INDIVIDUALS EXPERIENCE.PREREGISTRATION PROSPERO IDENTIFIER: CRD42022364720.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
9 1345  32 DETECTION OF DIFFERENTIALLY METHYLATED REGIONS USING BAYES FACTOR FOR ORDINAL GROUP RESPONSES. RESEARCHERS IN GENOMICS ARE INCREASINGLY INTERESTED IN EPIGENETIC FACTORS SUCH AS DNA METHYLATION, BECAUSE THEY PLAY AN IMPORTANT ROLE IN REGULATING GENE EXPRESSION WITHOUT CHANGES IN THE DNA SEQUENCE. THERE HAVE BEEN SIGNIFICANT ADVANCES IN DEVELOPING STATISTICAL METHODS TO DETECT DIFFERENTIALLY METHYLATED REGIONS (DMRS) ASSOCIATED WITH BINARY DISEASE STATUS. MOST OF THESE METHODS ARE BEING DEVELOPED FOR DETECTING DIFFERENTIAL METHYLATION RATES BETWEEN CASES AND CONTROLS. WE CONSIDER MULTIPLE SEVERITY LEVELS OF DISEASE, AND DEVELOP A BAYESIAN STATISTICAL METHOD TO DETECT THE REGION WITH INCREASING (OR DECREASING) METHYLATION RATES AS THE DISEASE SEVERITY INCREASES. PATIENTS ARE CLASSIFIED INTO MORE THAN TWO GROUPS, BASED ON THE DISEASE SEVERITY (E.G., STAGES OF CANCER), AND DMRS ARE DETECTED BY USING MOVING WINDOWS ALONG THE GENOME. WITHIN EACH WINDOW, THE BAYES FACTOR IS CALCULATED TO TEST THE HYPOTHESIS OF MONOTONIC INCREASE IN METHYLATION RATES CORRESPONDING TO SEVERITY OF THE DISEASE VERSUS NO DIFFERENCE. A MIXED-EFFECT MODEL IS USED TO INCORPORATE THE CORRELATION OF METHYLATION RATES OF NEARBY CPG SITES IN THE REGION. RESULTS FROM EXTENSIVE SIMULATION INDICATE THAT OUR PROPOSED METHOD IS STATISTICALLY VALID AND REASONABLY POWERFUL. WE DEMONSTRATE OUR APPROACH ON A BISULFITE SEQUENCING DATASET FROM A CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) STUDY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
10 5638  35 SERUM METABOLOMICS REVEALS PATHWAYS AND BIOMARKERS ASSOCIATED WITH ASTHMA PATHOGENESIS. BACKGROUND: ASTHMA IS A CHRONIC INFLAMMATORY DISEASE CAUSED BY COMPLEX INTERACTIONS OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. FOR THIS REASON, NEW APPROACHES ARE REQUIRED TO CLARIFY THE PATHOGENESIS OF ASTHMA BY SYSTEMIC REVIEW. OBJECTIVE: WE APPLIED A (1)H-NMR METABOLOMICS APPROACH TO INVESTIGATE THE ALTERED METABOLIC PATTERN IN SERA FROM PATIENTS WITH ASTHMA AND SOUGHT TO IDENTIFY THE MECHANISM UNDERLYING ASTHMA AND POTENTIAL BIOMARKERS. METHOD: A GLOBAL PROFILE OF SERA FROM PATIENTS WITH ASTHMA (N = 39) AND CONTROLS (N = 26) WAS GENERATED USING (1)H-NMR SPECTROSCOPY COUPLED WITH MULTIVARIATE STATISTICAL ANALYSIS. ENDOGENOUS METABOLITES IN SERUM WERE RAPIDLY MEASURED USING THE TARGET-PROFILING PROCEDURE. RESULTS: MULTIVARIATE STATISTICAL ANALYSIS SHOWED A CLEAR DISTINCTION BETWEEN PATIENTS WITH ASTHMA AND HEALTHY SUBJECTS. SERA OF ASTHMA PATIENTS WERE CHARACTERIZED BY INCREASED LEVELS OF METHIONINE, GLUTAMINE, AND HISTIDINE AND BY DECREASED LEVELS OF FORMATE, METHANOL, ACETATE, CHOLINE, O-PHOSPHOCHOLINE, ARGININE, AND GLUCOSE. THE METABOLITES DETECTED IN THE SERA OF PATIENTS WITH ASTHMA ARE INVOLVED IN HYPERMETHYLATION, RESPONSE TO HYPOXIA, AND IMMUNE REACTION. FURTHERMORE, THE LEVELS OF SERUM METABOLITES FROM PATIENTS WITH ASTHMA CORRELATED WITH ASTHMA SEVERITY; IN PARTICULAR, LIPID METABOLISM WAS ALTERED IN PATIENTS WITH LOWER FORCED EXPIRATORY VOLUME IN 1 S PERCENTAGE (FEV(1)%) PREDICTED VALUES. IN ADDITION, POTENTIAL BIOMARKERS SHOWED STRONG PREDICTIVE POWER IN ROC ANALYSIS, AND THE PRESENCE OF ASTHMA IN EXTERNAL VALIDATION MODELS WAS PREDICTED WITH HIGH ACCURACY (90.9% FOR ASTHMA AND 100% FOR CONTROL SUBJECTS). CONCLUSION & CLINICAL RELEVANCE: THESE DATA SHOWED THAT (1)H-NMR-BASED METABOLITE PROFILING OF SERUM MAY BE USEFUL FOR THE EFFECTIVE DIAGNOSIS OF ASTHMA AND A FURTHER UNDERSTANDING OF ITS PATHOGENESIS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
11 6405  39 THE SARS-COV-2 RECEPTOR ANGIOTENSIN-CONVERTING ENZYME 2 (ACE2) IN MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME: ANALYSIS OF HIGH-THROUGHPUT EPIGENETIC AND GENE EXPRESSION STUDIES. PATIENTS AFFECTED BY MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) SHOW SPECIFIC EPIGENETIC AND GENE EXPRESSION SIGNATURES OF THE DISEASE. HOWEVER, IT IS UNKNOWN WHETHER THESE SIGNATURES INCLUDE ABNORMAL LEVELS OF THE HUMAN ANGIOTENSIN-CONVERTING ENZYMES, ACE AND ACE2, THE LATTER BEING THE MAIN RECEPTOR DESCRIBED FOR THE HOST-CELL INVASION BY SARS-COV-2. TO INVESTIGATE THAT, WE FIRST RE-ANALYZED AVAILABLE CASE-CONTROL EPIGENOME-WIDE ASSOCIATION STUDIES BASED ON DNA METHYLATION DATA, AND CASE-CONTROL GENE EXPRESSION STUDIES BASED ON MICROARRAY DATA. FROM THESE PUBLISHED STUDIES, WE FOUND AN ASSOCIATION BETWEEN ME/CFS AND 4 POTENTIALLY HYPOMETHYLATED PROBES LOCATED IN THE ACE LOCUS. WE ALSO FOUND ANOTHER DISEASE ASSOCIATION WITH ONE HYPOMETHYLATED PROBE LOCATED IN THE TRANSCRIPTION START SITE OF ACE2. THE SAME DISEASE ASSOCIATIONS WERE OBTAINED FOR WOMEN BUT NOT FOR MEN AFTER PERFORMING SEX-SPECIFIC ANALYSES. IN CONTRAST, A META-ANALYSIS OF GENE EXPRESSION LEVELS COULD NOT PROVIDE EVIDENCE FOR A DIFFERENTIALLY EXPRESSION OF ACE AND ACE2 IN AFFECTED PATIENTS WHEN COMPARED TO HEALTHY CONTROLS. IN LINE WITH THIS NEGATIVE FINDING, THE ANALYSIS OF A NEW DATA SET ON THE GENE EXPRESSION OF ACE AND ACE2 IN PERIPHERAL BLOOD MONONUCLEAR CELLS DID NOT FIND ANY DIFFERENCES BETWEEN A FEMALE COHORT OF 37 PATIENTS AND 34 AGE-MATCHED HEALTHY CONTROLS. FUTURE STUDIES SHOULD BE CONDUCTED TO EXTEND THIS INVESTIGATION TO OTHER POTENTIAL RECEPTORS USED BY SARS-COV-2. THESE STUDIES WILL HELP RESEARCHERS AND CLINICIANS TO IMPROVE THE UNDERSTANDING OF THE HEALTH RISK IMPOSED BY THIS VIRUS WHEN INFECTING PATIENTS AFFECTED BY THIS DEBILITATING DISEASE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
12 2815  29 FIBROMYALGIA: GENETICS AND EPIGENETICS INSIGHTS MAY PROVIDE THE BASIS FOR THE DEVELOPMENT OF DIAGNOSTIC BIOMARKERS. FIBROMYALGIA IS A DISEASE CHARACTERIZED BY CHRONIC WIDESPREAD PAIN WITH ADDITIONAL SYMPTOMS, SUCH AS JOINT STIFFNESS, FATIGUE, SLEEP DISTURBANCE, COGNITIVE DYSFUNCTION, AND DEPRESSION. CURRENTLY, FIBROMYALGIA DIAGNOSIS IS BASED EXCLUSIVELY ON A COMPREHENSIVE CLINICAL ASSESSMENT, ACCORDING TO 2016 ACR CRITERIA, BUT VALIDATED BIOLOGICAL BIOMARKERS ASSOCIATED WITH FIBROMYALGIA HAVE NOT YET BEEN IDENTIFIED. GENOME-WIDE ASSOCIATION STUDIES INVESTIGATED GENES POTENTIALLY INVOLVED IN FIBROMYALGIA PATHOGENESIS HIGHLIGHTING THAT GENETIC FACTORS ARE POSSIBLY RESPONSIBLE FOR UP TO 50% OF THE DISEASE SUSCEPTIBILITY. POTENTIAL CANDIDATE GENES FOUND ASSOCIATED TO FIBROMYALGIA ARE SLC64A4, TRPV2, MYT1L, AND NRXN3. FURTHERMORE, A GENE-ENVIRONMENTAL INTERACTION HAS BEEN PROPOSED AS TRIGGERING MECHANISM, THROUGH EPIGENETIC ALTERATIONS: IN PARTICULAR, FIBROMYALGIA APPEARS TO BE CHARACTERIZED BY A HYPOMETHYLATED DNA PATTERN, IN GENES IMPLICATED IN STRESS RESPONSE, DNA REPAIR, AUTONOMIC SYSTEM RESPONSE, AND SUBCORTICAL NEURONAL ABNORMALITIES. DIFFERENCES IN THE GENOME-WIDE EXPRESSION PROFILE OF MICRORNAS WERE FOUND AMONG MULTIPLE TISSUES, INDICATING THE INVOLVEMENT OF DISTINCT PROCESSES IN FIBROMYALGIA PATHOGENESIS. FURTHER STUDIES SHOULD BE DEDICATED TO STRENGTH THESE PRELIMINARY FINDINGS, IN LARGER MULTICENTER COHORTS, TO IDENTIFY RELIABLE DIRECTIONS FOR BIOMARKER RESEARCH AND CLINICAL PRACTICE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
13 6547  38 TRANSCRIPTOMICS OF LONG-TERM MEDITATION PRACTICE: EVIDENCE FOR PREVENTION OR REVERSAL OF STRESS EFFECTS HARMFUL TO HEALTH. BACKGROUND AND OBJECTIVES: STRESS CAN OVERLOAD ADAPTIVE MECHANISMS, LEADING TO EPIGENETIC EFFECTS HARMFUL TO HEALTH. RESEARCH ON THE REVERSAL OF THESE EFFECTS IS IN ITS INFANCY. EARLY RESULTS SUGGEST SOME MEDITATION TECHNIQUES HAVE HEALTH BENEFITS THAT GROW WITH REPEATED PRACTICE. THIS STUDY FOCUSED ON POSSIBLE TRANSCRIPTOMIC EFFECTS OF 38 YEARS OF TWICE-DAILY TRANSCENDENTAL MEDITATION((R)) (TM((R))) PRACTICE. MATERIALS AND METHODS: FIRST, USING ILLUMINA((R)) BEADCHIP MICROARRAY TECHNOLOGY, DIFFERENCES IN GLOBAL GENE EXPRESSION IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) WERE SOUGHT BETWEEN HEALTHY PRACTITIONERS AND TIGHTLY MATCHED CONTROLS (N = 12, AGE 65). SECOND, THESE MICROARRAY RESULTS WERE VERIFIED ON A SUBSET OF GENES USING QUANTITATIVE POLYMERASE CHAIN REACTION (QPCR) AND WERE VALIDATED USING QPCR IN LARGER TM AND CONTROL GROUPS (N = 45, AGE 63). BIOINFORMATICS INVESTIGATION EMPLOYED INGENUITY((R)) PATHWAY ANALYSIS (IPA((R))), DAVID, GENOMATIX, AND R PACKAGES. RESULTS: THE 200 GENES AND LOCI FOUND TO MEET STRICT CRITERIA FOR DIFFERENTIAL EXPRESSION IN THE MICROARRAY EXPERIMENT SHOWED CONTRASTING PATTERNS OF EXPRESSION THAT DISTINGUISHED THE TWO GROUPS. DIFFERENTIAL EXPRESSION RELATING TO IMMUNE FUNCTION AND ENERGY EFFICIENCY WERE MOST APPARENT. IN THE TM GROUP, RELATIVE TO THE CONTROL, ALL 49 GENES ASSOCIATED WITH INFLAMMATION WERE DOWNREGULATED, WHILE GENES ASSOCIATED WITH ANTIVIRAL AND ANTIBODY COMPONENTS OF THE DEFENSE RESPONSE WERE UPREGULATED. THE LARGEST EXPRESSION DIFFERENCES WERE SHOWN BY SIX GENES RELATED TO ERYTHROCYTE FUNCTION THAT APPEARED TO REFLECT A CONDITION OF LOWER ENERGY EFFICIENCY IN THE CONTROL GROUP. RESULTS SUPPORTING THESE GENE EXPRESSION DIFFERENCES WERE OBTAINED WITH QPCR-MEASURED EXPRESSION BOTH IN THE WELL-MATCHED MICROARRAY GROUPS AND IN THE LARGER, LESS WELL-MATCHED GROUPS. CONCLUSIONS: THESE FINDINGS ARE CONSISTENT WITH PREDICTIONS BASED ON RESULTS FROM EARLIER RANDOMIZED TRIALS OF MEDITATION AND MAY PROVIDE EVIDENCE FOR STRESS-RELATED MOLECULAR MECHANISMS UNDERLYING REDUCTIONS IN ANXIETY, POST-TRAUMATIC STRESS DISORDER (PTSD), CARDIOVASCULAR DISEASE (CVD), AND OTHER CHRONIC DISORDERS AND DISEASES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
14 1537  29 DNA METHYLATION IN ADOLESCENTS WITH ANXIETY DISORDER: A LONGITUDINAL STUDY. ANXIETY DISORDERS (AD) TYPICALLY MANIFEST IN CHILDREN AND ADOLESCENTS AND MIGHT PERSIST INTO ADULTHOOD. HOWEVER, THERE ARE STILL FEW DATA CONCERNING EPIGENETIC MECHANISMS ASSOCIATED WITH ONSET, PERSISTENCE OR REMISSION OF AD OVER TIME. WE INVESTIGATED A COHORT OF ADOLESCENTS AND YOUNG ADULTS AT BASELINE (AGE; 13.19 +/- 2.38) AND AFTER 5 YEARS AND CLASSIFIED THEM ACCORDING TO THE AD DIAGNOSIS AND THEIR LONGITUDINAL TRAJECTORIES INTO 4 GROUPS: (1) TYPICALLY DEVELOPING COMPARISONS (TDC; CONTROL GROUP, N = 14); (2) INCIDENT (AD IN THE SECOND EVALUATION ONLY, N = 11); (3) PERSISTENT (AD IN BOTH EVALUATIONS, N = 14) AND (4) REMITTENT (AD IN THE FIRST EVALUATION ONLY, N = 8). DNA METHYLATION WAS EVALUATED WITH THE INFINIUM HUMANMETHYLATION450 BEADCHIP FROM SALIVA SAMPLES COLLECTED AT BOTH EVALUATIONS. GENE SET ENRICHMENT ANALYSIS WAS APPLIED TO CONSIDER BIOLOGICAL PATHWAYS. WE FOUND DECREASED DNA METHYLATION IN TDC GROUP WHILE THE CHRONIC CASES OF AD PRESENTED HYPERMETHYLATION IN CENTRAL NERVOUS SYSTEM DEVELOPMENT PATHWAYS. MOREOVER, WE SHOWED THAT THIS PERSISTENT GROUP ALSO PRESENTED HYPERMETHYLATION WHILE THE OTHER THREE GROUPS WERE ASSOCIATED WITH HYPOMETHYLATION IN NERVOUS SYSTEM DEVELOPMENT PATHWAY. INCIDENCE AND REMISSION GROUPS WERE ASSOCIATED WITH INCREASED AND DECREASED METHYLATION IN NEURON DEVELOPMENT PATHWAYS, RESPECTIVELY. LARGER STUDIES ARE LIKELY TO DETECT SPECIFIC GENES RELEVANT TO AD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
15  639  39 BIOMARKERS FOR MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS): A SYSTEMATIC REVIEW. BACKGROUND: MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A MULTIFACETED CONDITION THAT AFFECTS MOST BODY SYSTEMS. THERE IS CURRENTLY NO KNOWN DIAGNOSTIC BIOMARKER; INSTEAD, DIAGNOSIS IS DEPENDENT ON APPLICATION OF SYMPTOM-BASED CASE CRITERIA FOLLOWING EXCLUSION OF ANY OTHER POTENTIAL MEDICAL CONDITIONS. WHILE THERE ARE SOME STUDIES THAT REPORT POTENTIAL BIOMARKERS FOR ME/CFS, THEIR EFFICACY HAS NOT BEEN VALIDATED. THE AIM OF THIS SYSTEMATIC REVIEW IS TO COLLATE AND APPRAISE LITERATURE PERTAINING TO A POTENTIAL BIOMARKER(S) WHICH MAY EFFECTIVELY DIFFERENTIATE ME/CFS PATIENTS FROM HEALTHY CONTROLS. METHODS: THIS SYSTEMATIC REVIEW WAS CONDUCTED ACCORDING TO THE PREFERRED REPORTING ITEMS FOR SYSTEMATIC REVIEWS AND META-ANALYSES AND COCHRANE REVIEW GUIDELINES. PUBMED, EMBASE AND SCOPUS WERE SYSTEMATICALLY SEARCHED FOR ARTICLES CONTAINING "BIOMARKER" AND "ME/CFS" KEYWORDS IN THE ABSTRACT OR TITLE AND IF THEY INCLUDED THE FOLLOWING CRITERIA: (1) WERE OBSERVATIONAL STUDIES PUBLISHED BETWEEN DECEMBER 1994 AND APRIL 2022; (2) INVOLVED ADULT HUMAN PARTICIPANTS; (3) FULL TEXT IS AVAILABLE IN ENGLISH (4) ORIGINAL RESEARCH; (5) DIAGNOSIS OF ME/CFS PATIENTS MADE ACCORDING TO THE FUKUDA CRITERIA (1994), CANADIAN CONSENSUS CRITERIA (2003), INTERNATIONAL CONSENSUS CRITERIA (2011) OR INSTITUTE OF MEDICINE CRITERIA (2015); (6) STUDY INVESTIGATED POTENTIAL BIOMARKERS OF ME/CFS COMPARED TO HEALTHY CONTROLS. QUALITY AND BIAS WERE ASSESSED USING THE JOANNA BRIGGS INSTITUTE CRITICAL APPRAISAL CHECKLIST FOR CASE CONTROL STUDIES. RESULTS: A TOTAL OF 101 PUBLICATIONS WERE INCLUDED IN THIS SYSTEMATIC REVIEW. POTENTIAL BIOMARKERS RANGED FROM GENETIC/EPIGENETIC (19.8%), IMMUNOLOGICAL (29.7%), METABOLOMICS/MITOCHONDRIAL/MICROBIOME (14.85%), ENDOVASCULAR/CIRCULATORY (17.82%), NEUROLOGICAL (7.92%), ION CHANNEL (8.91%) AND PHYSICAL DYSFUNCTION BIOMARKERS (8.91%). MOST OF THE POTENTIAL BIOMARKERS REPORTED WERE BLOOD-BASED (79.2%). USE OF LYMPHOCYTES AS A MODEL TO INVESTIGATE ME/CFS PATHOLOGY WAS PROMINENT AMONG IMMUNE-BASED BIOMARKERS. MOST BIOMARKERS HAD SECONDARY (43.56%) OR TERTIARY (54.47%) SELECTIVITY, WHICH IS THE ABILITY FOR THE BIOMARKER TO IDENTIFY A DISEASE-CAUSING AGENT, AND A MODERATE (59.40%) TO COMPLEX (39.60%) EASE-OF-DETECTION, INCLUDING THE REQUIREMENT OF SPECIALISED EQUIPMENT. CONCLUSIONS: ALL POTENTIAL ME/CFS BIOMARKERS DIFFERED IN EFFICIENCY, QUALITY, AND TRANSLATABILITY AS A DIAGNOSTIC MARKER. REPRODUCIBILITY OF FINDINGS BETWEEN THE INCLUDED PUBLICATIONS WERE LIMITED, HOWEVER, SEVERAL STUDIES VALIDATED THE INVOLVEMENT OF IMMUNE DYSFUNCTION IN THE PATHOLOGY OF ME/CFS AND THE USE OF LYMPHOCYTES AS A MODEL TO INVESTIGATE THE PATHOMECHANISM OF ILLNESS. THE HETEROGENEITY SHOWN ACROSS MANY OF THE INCLUDED STUDIES HIGHLIGHTS THE NEED FOR MULTIDISCIPLINARY RESEARCH AND UNIFORM PROTOCOLS IN ME/CFS BIOMARKER RESEARCH.	2023	

16  177  29 ACCELERATED EPIGENETIC AGING AND INFLAMMATORY/IMMUNOLOGICAL PROFILE (IPAGE) IN PATIENTS WITH CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS DEFINED BY A REDUCED ESTIMATED GLOMERULAR FILTRATION RATE (EGFR). THIS FAILURE CAN BE RELATED TO A PHENOTYPE OF ACCELERATED AGING. IN THIS WORK, WE CONSIDERED 76 PATIENTS WITH END-STAGE RENAL DISEASE (ESRD) AND 83 HEALTHY CONTROLS. WE CONCOMITANTLY EVALUATED FOR THE FIRST TIME TWO MEASURES THAT CAN BE INFORMATIVE OF THE RATE OF AGING, I.E., WHOLE BLOOD DNA METHYLATION USING THE ILLUMINA INFINIUM EPIC ARRAY AND PLASMA LEVELS OF A SELECTION OF INFLAMMATORY/IMMUNOLOGICAL PROTEINS USING MULTIPLEX IMMUNOASSAYS. FIRST OF ALL, WE DEMONSTRATED ACCELERATED AGING IN TERMS OF THE MOST COMMON EPIGENETIC AGE ESTIMATORS IN CKD PATIENTS. MOREOVER, WE DEVELOPED A NEW CLOCK/PREDICTOR OF AGE BASED ON THE INFLAMMATORY/IMMUNOLOGICAL PROFILE (IPAGE) AND IDENTIFIED THE INFLAMMATORY/IMMUNOLOGICAL BIOMARKERS DIFFERENTIALLY EXPRESSED BETWEEN CASES AND CONTROLS. IPAGE APPEARED TO BE MORE SENSITIVE THAN EPIGENETIC CLOCKS IN QUANTIFYING THE ACCELERATED AGING PHENOTYPE OF ESRD PATIENTS. INTERESTINGLY, WE DID NOT FIND ANY CORRELATION BETWEEN THE AGE ACCELERATION EVALUATED ACCORDING TO THE EPIGENETIC CLOCKS AND IPAGE IN EITHER THE ESRD GROUP OR THE CONTROL GROUP. ON THE WHOLE, OUR DATA SHOW A CONSISTENT ACCELERATED AGING PHENOTYPE IN ESRD PATIENTS, WHICH IS BETTER APPRECIATED BY QUANTIFYING THE UNDERLYING INFLAMMATORY PROCESSES (INFLAMMAGING) BY IPAGE THAN BY USING EPIGENETIC CLOCKS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
17 2820  29 FINE-MAPPING INFLAMMATORY BOWEL DISEASE LOCI TO SINGLE-VARIANT RESOLUTION. INFLAMMATORY BOWEL DISEASES ARE CHRONIC GASTROINTESTINAL INFLAMMATORY DISORDERS THAT AFFECT MILLIONS OF PEOPLE WORLDWIDE. GENOME-WIDE ASSOCIATION STUDIES HAVE IDENTIFIED 200 INFLAMMATORY BOWEL DISEASE-ASSOCIATED LOCI, BUT FEW HAVE BEEN CONCLUSIVELY RESOLVED TO SPECIFIC FUNCTIONAL VARIANTS. HERE WE REPORT FINE-MAPPING OF 94 INFLAMMATORY BOWEL DISEASE LOCI USING HIGH-DENSITY GENOTYPING IN 67,852 INDIVIDUALS. WE PINPOINT 18 ASSOCIATIONS TO A SINGLE CAUSAL VARIANT WITH GREATER THAN 95% CERTAINTY, AND AN ADDITIONAL 27 ASSOCIATIONS TO A SINGLE VARIANT WITH GREATER THAN 50% CERTAINTY. THESE 45 VARIANTS ARE SIGNIFICANTLY ENRICHED FOR PROTEIN-CODING CHANGES (N = 13), DIRECT DISRUPTION OF TRANSCRIPTION-FACTOR BINDING SITES (N = 3), AND TISSUE-SPECIFIC EPIGENETIC MARKS (N = 10), WITH THE LAST CATEGORY SHOWING ENRICHMENT IN SPECIFIC IMMUNE CELLS AMONG ASSOCIATIONS STRONGER IN CROHN'S DISEASE AND IN GUT MUCOSA AMONG ASSOCIATIONS STRONGER IN ULCERATIVE COLITIS. THE RESULTS OF THIS STUDY SUGGEST THAT HIGH-RESOLUTION FINE-MAPPING IN LARGE SAMPLES CAN CONVERT MANY DISCOVERIES FROM GENOME-WIDE ASSOCIATION STUDIES INTO STATISTICALLY CONVINCING CAUSAL VARIANTS, PROVIDING A POWERFUL SUBSTRATE FOR EXPERIMENTAL ELUCIDATION OF DISEASE MECHANISMS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
18 1026  52 CIRCULATING MIRNAS EXPRESSION IN MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME. MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A COMPLEX MULTIFACTORIAL DISEASE THAT CAUSES INCREASING MORBIDITY WORLDWIDE, AND MANY INDIVIDUALS WITH ME/CFS SYMPTOMS REMAIN UNDIAGNOSED DUE TO THE LACK OF DIAGNOSTIC BIOMARKERS. ITS ETIOLOGY IS STILL UNKNOWN, BUT INCREASING EVIDENCE SUPPORTS A ROLE OF HERPESVIRUSES (INCLUDING HHV-6A AND HHV-6B) AS POTENTIAL TRIGGERS. INTERESTINGLY, THE INFECTION BY THESE VIRUSES HAS BEEN REPORTED TO IMPACT THE EXPRESSION OF MICRORNAS (MIRNAS), SHORT NON-CODING RNA SEQUENCES WHICH HAVE BEEN SUGGESTED TO BE EPIGENETIC FACTORS MODULATING ME/CFS PATHOGENIC MECHANISMS. NOTABLY, THE PRESENCE OF CIRCULATING MIRNAS IN PLASMA HAS RAISED THE POSSIBILITY TO USE THEM AS VALUABLE BIOMARKERS FOR DISTINGUISHING ME/CFS PATIENTS FROM HEALTHY CONTROLS. THUS, THIS STUDY AIMED AT DETERMINING THE ROLE OF EIGHT MIRNAS, WHICH WERE SELECTED FOR THEIR PREVIOUS ASSOCIATION WITH ME/CFS, AS POTENTIAL CIRCULATING BIOMARKERS OF THE DISEASE. THEIR PRESENCE WAS QUANTITATIVELY EVALUATED IN PLASMA FROM 40 ME/CFS PATIENTS AND 20 HEALTHY CONTROLS BY SPECIFIC TAQMAN ASSAYS, AND THE RESULTS SHOWED THAT SIX OUT OF THE EIGHT OF THE SELECTED MIRNAS WERE DIFFERENTLY EXPRESSED IN PATIENTS COMPARED TO CONTROLS; MORE SPECIFICALLY, FIVE MIRNAS WERE SIGNIFICANTLY UPREGULATED (MIR-127-3P, MIR-142-5P, MIR-143-3P, MIR-150-5P, AND MIR-448), AND ONE WAS DOWNMODULATED (MIR-140-5P). MIRNA LEVELS DIRECTLY CORRELATED WITH DISEASE SEVERITY, WHEREAS NO SIGNIFICANT CORRELATIONS WERE OBSERVED WITH THE PLASMA LEVELS OF SEVEN PRO-INFLAMMATORY CYTOKINES OR WITH THE PRESENCE/LOAD OF HHV-6A/6B GENOME, AS JUDGED BY SPECIFIC PCR AMPLIFICATION. THE RESULTS MAY OPEN THE WAY FOR FURTHER VALIDATION OF MIRNAS AS NEW POTENTIAL BIOMARKERS IN ME/CFS AND INCREASE THE KNOWLEDGE OF THE COMPLEX PATHWAYS INVOLVED IN THE ME/CFS DEVELOPMENT.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
19  812  48 CHANGES IN DNA METHYLATION PROFILES OF MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME PATIENTS REFLECT SYSTEMIC DYSFUNCTIONS. BACKGROUND: MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A LIFELONG DEBILITATING DISEASE WITH A COMPLEX PATHOLOGY NOT YET CLEARLY DEFINED. SUSCEPTIBILITY TO ME/CFS INVOLVES GENETIC PREDISPOSITION AND EXPOSURE TO ENVIRONMENTAL FACTORS, SUGGESTING AN EPIGENETIC ASSOCIATION. EPIGENETIC STUDIES WITH OTHER ME/CFS COHORTS HAVE USED ARRAY-BASED TECHNOLOGY TO IDENTIFY DIFFERENTIALLY METHYLATED INDIVIDUAL SITES. CHANGES IN RNA QUANTITIES AND PROTEIN ABUNDANCE HAVE BEEN DOCUMENTED IN OUR PREVIOUS INVESTIGATIONS WITH THE SAME ME/CFS COHORT USED FOR THIS STUDY. RESULTS: DNA FROM A WELL-CHARACTERISED NEW ZEALAND COHORT OF 10 ME/CFS PATIENTS AND 10 AGE-/SEX-MATCHED HEALTHY CONTROLS WAS ISOLATED FROM PERIPHERAL BLOOD MONONUCLEAR (PBMC) CELLS, AND USED TO GENERATE REDUCED GENOME-SCALE DNA METHYLATION MAPS USING REDUCED REPRESENTATION BISULPHITE SEQUENCING (RRBS). THE SEQUENCING DATA WERE ANALYSED UTILISING THE DMAP ANALYSIS PIPELINE TO IDENTIFY DIFFERENTIALLY METHYLATED FRAGMENTS, AND THE METHYLKIT PIPELINE WAS USED TO QUANTIFY METHYLATION DIFFERENCES AT INDIVIDUAL CPG SITES. DMAP IDENTIFIED 76 DIFFERENTIALLY METHYLATED FRAGMENTS AND METHYLKIT IDENTIFIED 394 DIFFERENTIALLY METHYLATED CYTOSINES THAT INCLUDED BOTH HYPER- AND HYPO-METHYLATION. FOUR CLUSTERS WERE IDENTIFIED WHERE DIFFERENTIALLY METHYLATED DNA FRAGMENTS OVERLAPPED WITH OR WERE WITHIN CLOSE PROXIMITY TO MULTIPLE DIFFERENTIALLY METHYLATED INDIVIDUAL CYTOSINES. THESE CLUSTERS IDENTIFIED REGULATORY REGIONS FOR 17 PROTEIN ENCODING GENES RELATED TO METABOLIC AND IMMUNE ACTIVITY. ANALYSIS OF DIFFERENTIALLY METHYLATED GENE BODIES (EXONS/INTRONS) IDENTIFIED 122 UNIQUE GENES. COMPARISON WITH OTHER STUDIES ON PBMCS FROM ME/CFS PATIENTS AND CONTROLS WITH ARRAY TECHNOLOGY SHOWED 59% OF THE GENES IDENTIFIED IN THIS STUDY WERE ALSO FOUND IN ONE OR MORE OF THESE STUDIES. FUNCTIONAL PATHWAY ENRICHMENT ANALYSIS IDENTIFIED 30 ASSOCIATED PATHWAYS. THESE INCLUDED IMMUNE, METABOLIC AND NEUROLOGICAL-RELATED FUNCTIONS DIFFERENTIALLY REGULATED IN ME/CFS PATIENTS COMPARED TO THE MATCHED HEALTHY CONTROLS. CONCLUSIONS: MAJOR DIFFERENCES WERE IDENTIFIED IN THE DNA METHYLATION PATTERNS OF ME/CFS PATIENTS THAT CLEARLY DISTINGUISHED THEM FROM THE HEALTHY CONTROLS. OVER HALF FOUND IN GENE BODIES WITH RRBS IN THIS STUDY HAD BEEN IDENTIFIED IN OTHER ME/CFS STUDIES USING THE SAME CELLS BUT WITH ARRAY TECHNOLOGY. WITHIN THE ENRICHED FUNCTIONAL IMMUNE, METABOLIC AND NEUROLOGICAL PATHWAYS, A NUMBER OF ENRICHED NEUROTRANSMITTER AND NEUROPEPTIDE REACTOME PATHWAYS HIGHLIGHTED A DISTURBED NEUROLOGICAL PATHOPHYSIOLOGY WITHIN THE PATIENT GROUP.	2020	
                                                                                                                                                                                                                           
20 1739  41 EARLY DNA METHYLATION CHANGES IN CHILDREN DEVELOPING BETA CELL AUTOIMMUNITY AT A YOUNG AGE. AIMS/HYPOTHESIS: TYPE 1 DIABETES IS A CHRONIC AUTOIMMUNE DISEASE OF COMPLEX AETIOLOGY, INCLUDING A POTENTIAL ROLE FOR EPIGENETIC REGULATION. PREVIOUS EPIGENOMIC STUDIES FOCUSED MAINLY ON CLINICALLY DIAGNOSED INDIVIDUALS. THE AIM OF THE STUDY WAS TO ASSESS EARLY DNA METHYLATION CHANGES ASSOCIATED WITH TYPE 1 DIABETES ALREADY BEFORE THE DIAGNOSIS OR EVEN BEFORE THE APPEARANCE OF AUTOANTIBODIES. METHODS: REDUCED REPRESENTATION BISULPHITE SEQUENCING (RRBS) WAS APPLIED TO STUDY DNA METHYLATION IN PURIFIED CD4(+) T CELL, CD8(+) T CELL AND CD4(-)CD8(-) CELL FRACTIONS OF 226 PERIPHERAL BLOOD MONONUCLEAR CELL SAMPLES LONGITUDINALLY COLLECTED FROM SEVEN TYPE 1 DIABETES-SPECIFIC AUTOANTIBODY-POSITIVE INDIVIDUALS AND CONTROL INDIVIDUALS MATCHED FOR AGE, SEX, HLA RISK AND PLACE OF BIRTH. WE ALSO EXPLORED CORRELATIONS BETWEEN DNA METHYLATION AND GENE EXPRESSION USING RNA SEQUENCING DATA FROM THE SAME SAMPLES. TECHNICAL VALIDATION OF RRBS RESULTS WAS PERFORMED USING PYROSEQUENCING. RESULTS: WE IDENTIFIED 79, 56 AND 45 DIFFERENTIALLY METHYLATED REGIONS IN CD4(+) T CELLS, CD8(+) T CELLS AND CD4(-)CD8(-) CELL FRACTIONS, RESPECTIVELY, BETWEEN TYPE 1 DIABETES-SPECIFIC AUTOANTIBODY-POSITIVE INDIVIDUALS AND CONTROL PARTICIPANTS. THE ANALYSIS OF PRE-SEROCONVERSION SAMPLES IDENTIFIED DNA METHYLATION SIGNATURES AT THE VERY EARLY STAGE OF DISEASE, INCLUDING DIFFERENTIAL METHYLATION AT THE PROMOTER OF IRF5 IN CD4(+) T CELLS. FURTHER, WE VALIDATED RRBS RESULTS USING PYROSEQUENCING AT THE FOLLOWING CPG SITES: CHR19:18118304 IN THE PROMOTER OF ARRDC2; CHR21:47307815 IN THE INTRON OF PCBP3; AND CHR14:81128398 IN THE INTERGENIC REGION NEAR TRAF3 IN CD4(+) T CELLS. CONCLUSIONS/INTERPRETATION: THESE PRELIMINARY RESULTS PROVIDE NOVEL INSIGHTS INTO CELL TYPE-SPECIFIC DIFFERENTIAL EPIGENETIC REGULATION OF GENES, WHICH MAY CONTRIBUTE TO TYPE 1 DIABETES PATHOGENESIS AT THE VERY EARLY STAGE OF DISEASE DEVELOPMENT. SHOULD THESE FINDINGS BE VALIDATED, THEY MAY SERVE AS A POTENTIAL SIGNATURE USEFUL FOR DISEASE PREDICTION AND MANAGEMENT.	2022